This invention relates to novel methyl esters of substituted 4-oxo-2-butenoic acid and more particularly to certain moieties of these novel compounds and their close derivatives as well as to the methods of their production and to the use of these compounds as bacteriostatic agents (a chemical agent that stops or inhibits the multiplication of bacteria) for humans or non-humans against Mycobacterium tuberculosis, and claims the benefit of priority of U.S. Provisional Application Ser. No. 60/292,985 filed May 23, 2001.
The infectious disease, tuberculosis (TB), is the leading cause of death worldwide from a single human pathogen, claiming more adult lives than diseases such as acquired immunodeficiency syndrome (AIDS), malaria, diarrhea, leprosy and all other tropical diseases combined (Zumla A, Grange J. B M J (1998) 316, 1962-1964). The organism usually responsible is the tubercle bacillus, Mycobacterium tuberculosis (MT), discovered by Robert Koch in 1882. However, M. bovis, which infects cattle may also infect man and M. africanum is a cause of TB in West Africa. Furthermore, a number of normally non-pathogenic mycobacteria, especially M. avium, M. intracellulare and M. scrofulaceum, cause opportunistic infectious disease in patients with AIDS (Horne N. 1996. Tuberculosis and other mycobacteria diseases. In Mansons Tropical Diseases, 20th edn, Cook FEG (ed). WB Saunders: London; 971-1015). Pulmonary TB, the most common type of the disease, is usually acquired by inhalation of the bacillus from an infectious patient and causes irreversible lung destruction.
About one third of the world""s population is currently infected with M. tuberculosis; 10% of those infected will develop clinical diseases, particularly those who also have the human immunodeficiency virus (HIV) infection (Zumla A, Grange J. B M J (1998) 316, 1962-1964). With the discovery of effective anti-mycobacteria agents (including ethambutol, isoniazid, pyrazinamide, rifampicin and streptomycin) and a reduction in poverty, there was a drastic decline in the number of TB cases, especially in developed nations. However, since the late 1980s, the number of cases of TB throughout the world has been increasing rapidly partly due to the emergence of multi-drug resistant M. tuberculosis (C. E. Barry, III, Biochemical Pharmacology (1997) 54, 1165-1172). According to the World Health Organization (World Health Organization. 1993 92. per Besra G S, Brennan P J. 1997. J Pharm Pharmacol 49 (Suppl. 1):25-30.s), it is expected that the annual death rate caused by TB will reach an overwhelming 3.5 million people by the year 2000. Thus the TB problem requires urgent attention. Short course anti-TB regiments initially using at least three first-line drugs (including isoniazid, rifampicin and pyrazinamide) are often not effective due to an increase in the number of tuberculosis strains that have become resistant to current drugs. For example the World Health Organization (WHO) recently reported that the death rate of patients with multi-drug resistant (MDR) tuberculosis in the US was approximately 70%. Current treatment is also very expensive: a 3 drugs regimen is needed (more than $500/month cost per patient). Thus the major problems faced in tuberculosis control are poor infrastructures for diagnosis and drug supply. The failure of patients to complete therapy as well as inappropriate mono-therapy has led to the emergence and distribution of strains of Mycobacterium tuberculosis resistant to every available chemotherapy (Bloom B R and Murray C J L, Science (1992) 257, 1055-1064). Such organisms will not remain confined to the Third World or to the poor and indigent of developed countries. The recent documentation of the spread of a single clone of multi-drug resistant Mycobacterium tuberculosis (the xe2x80x9cWxe2x80x9d strain) throughout the continental United States and Europe highlights the danger of an airborne pathogen in our global society (Bifani P J, et al., JAMA (1996) 275, 452-457).
The patent literature has numerous disclosures of Heterocyclic oxo-butenoic (crotonic) compounds: They include
Pamukci (6,232,312) describes crotonic acid derivatives (column 22, lines 43-58) for the treatment of colonic polyps;
Jones et al (6,121,450) discloses crotonic acid derivatives (column 8, line 34; column 78, line 24 and at example 340) as steroid modifiers in treating breast cancer (column 1, lines 55-58);
Kalden, et al (5,334,612) discloses compounds said to be useful for treating AIDS including derivatives of carboxylic acid (column 9, line 31) and pyrrolidine (column 7, line 24);
Nicolai, et al (6,180,651) discloses many anti-inflammatory and analgesic compounds, including adenocarcinoma (column 1, line 55), which includes heterocyclic alcohol-esters (column 11, lines 1-16) and butanoic acid derivatives (many Examples including 47 through 162);
Brown (6,066,670) describes an anti-viral admixture containing crotonic acid for treating tumors (see Abstract);
Girard, et al (5,308,852) discloses many compounds including butanoic acid derivatives (see Methods B and C of schemes II and III) which compounds which are said to inhibit tumor metastasis (column 7, line 56 and column 8, line 4);
Horwell, et al (5,580,896) discloses many heterocylic 4-oxo-2-butenoic acid derivatives (column 13, lines 21-59; also in columns 15+, examples 25,26,32,34,40,43-46, 77-79,97,99,103,106,), which are useful for inhibiting colorectal cancer (Abstract);
Giordani, et al (6,048,890) discloses 4-oxo-2-butenoic acid derivatives said to be useful for treatment of AIDS (column 1, line 8 and column 2, line 61; and,
Yonemeto, et al (6,083,985) recites a number of anti-tumor or anti-AIDS agents that include heterocylic butenoic acid derivatives.
For half a century, the most used anti-microbial agents referenced above for prophylaxis and treatment of tuberculosis since 1952 is isoniazid (isonicotinic acid hydrazide [INH]). One of the known complications of anti-tuberculosis chemotherapy caused by this drug is liver dysfunction plus a great number of other complications. The toxicity of INH is also a serious problem frequently resulting in poisoning. It is also known to be an acute/chronic hazards since INH is an irritant of the skin, eyes, mucous membranes and upper respiratory tract.
It appears from a review of the above that neither the heterocyclic oxo-butenoic compounds or the benzoxazine heterocyclic compounds of interest are disclosed nor is there any report of activity against Mycobacterium tuberculosis. 
Consequently, there is a need for an anti-tubercular drug for humans or non-humans which mitigates the above mentioned disadvantages of current bacteriostatic agents used as drugs against TB bacterium in humans.
The first objective of the present invention is to provide a bacteriostatic agent effective against Mycobacrium tuberculosis and other mycobacteria.
The second object of this invention is to provide a bacteriostatic agent that is effective in humans or non-humans against Mycobacterium tuberculosis and other mycobacteria.
A third object of this invention is to provide a bacteriostatic agent that is effective in humans or non-humans against Mycobacterium tuberculosis and other mycobacteria which is relatively inexpensive as a drug.
Another object of this invention is to provide novel methyl esters of substituted 4-oxo-2-butenoic acids.
A preferred embodiment of the invention encompasses a class of heterocyclics having the property of a bacteriostatic agent against Mycobacterium tuberculosis and other mycobacterium comprising methyl esters of substituted 4-oxo-2-butenoic acids and more specifically those derivatives: 4-(4-Ethoxyphenyl)-2-(Nxe2x80x2-fluoren-9-ylidenehydrazino)-4-oxobut-2-enoic acid methyl ester (OF-12); 4-(4-Ethoxyphenyl)-2-(Nxe2x80x2-fluoren-9-ylidenehydrazino)-2-hydroxy-4-oxo-butyric acid methyl ester (OF-13); 2-(4-Bromophenylamino)-5,5-dimethyl-4-oxohex-2-enoic acid methyl ester (OF-15); and the use of each in humans or non-humans as therapeutic means for the eradication of Mycobacterium tuberculosis and related mycobacteria from the humans and nonhumans.